Remote electronic control in the regioselective reduction of succinimides: A practical, scalable synthesis of EP4 antagonist MF-310

Article abstract of DOI:10.1021/jo901267x

(Chemical Equation Presented) A practical large-scale chromatography-free synthesis of EP4 antagonist MF-310, a potential new treatment for chronic inflammation, is presented. The synthetic route provided MF-310 as its sodium salt in 10 steps and 17% overall yield from commercially available pyridine dicarboxylate 7. The key features of this sequence include a unique regioselective reduction of succinimide 2 controlled by the electronic properties of a remote pyridine ring, preparation of cyclopropane carboxylic acid 3 via a Corey - Chaykovsky cyclopropanation, and a short synthesis of sulfonamide 5. 2009 American Chemical Society.

Full text of DOI:10.1021/jo901267x

pubs.acs.org/joc
in the treatment of chronic inflammation.3 To support
Remote Electronic Control in the Regioselective
Reduction of Succinimides: A Practical, Scalable
Synthesis of EP4 Antagonist MF-310
preclinical and clinical development of this compound, we
sought to develop a scalable synthesis of MF-310. We
describe herein a chromatography-free preparation of EP4
antagonist MF-310 on multikilogram scale that features the
use of an electronically controlled regioselective succinimide
reduction.
The retrosynthetic analysis of MF-310 suggests a logical
first disconnection between succinimide 2 and cyclopropane
carboxylic acid 3 (Scheme 1). Succinimide 2 could be ac-
cessed through a condensation of quinoline anhydride 4 with
sulfonamide 5. This strategy was attractive since it would
allow for a convergent synthesis, starting from easily acces-
sible, commercially available, starting materials 6, 7, and 8.
The success of this approach hinges on the ability to differ-
entiate between the two electronically biased carbonyl
groups of the succinimide moiety 2.
Carmela Molinaro,*,† Danny Gauvreau,†
Gregory Hughes,*,† Stephen Lau,† Sophie Lauzon,†
†
Remy Angelaud, Paul D. O’Shea, Jacob Janey,
†
‡
ꢀ
Michael Palucki,‡ Scott R. Hoerrner,‡ Conrad E. Raab,‡
Rick R. Sidler,‡ Michel Belley,§ and Yongxin Han§
†Departments of Process Research, Merck Frosst Centre for
Therapeutic Research, 16711 Trans Canada Highway,
Kirkland, Queꢀbec, Canada, H9H 3L1, ‡Process Research,
Merck Research Laboratories, P.O. Box 2000, Rahway, New
Jersey 07065, and §Medicinal Chemistry, Merck Frosst Centre
for Therapeutic Research, 16711 Trans Canada Highway,
Kirkland, Queꢀbec, Canada, H9H 3L1
The synthesis of sulfonamide intermediate 5 is outlined in
Scheme 2. Although there are several methods available for
the preparation of sulfonamides from sulfonyl chlorides and
amines or sulfinic acid salts (prepared from organolithium
or Grignard reagents) and an electrophilic nitrogen source,4
in our hands the methodology described by Wang5 produced
higher yield and purity material on large scale. Therefore,
under phase transfer catalysis conditions, the SN2 displace-
ment of benzylic bromide 8 with methyl 3-mercaptoproprio-
nate provided thioether 9 in 95% yield. The crude reaction
mixture was taken directly into the tungsten-catalyzed oxi-
dation, which afforded sulfone 10 in 95% yield.6,7 Inter-
mediate 11 can be prepared when sulfone 10 is treated with
sodium methoxide in methanol. However, careful monitor-
ing of the reaction revealed that 11 was thermally unstable
under anhydrous conditions and would extrude SO2 upon
carmela_molinaro@merck.com; greg_hughes@merck.com
Received June 18, 2009
A practical large-scale chromatography-free synthesis of
EP4 antagonist MF-310, a potential new treatment for
chronic inflammation, is presented. The synthetic route
provided MF-310 as its sodium salt in 10 steps and 17%
overall yield from commercially available pyridine dicar-
boxylate 7. The key features of this sequence include a
unique regioselective reduction of succinimide 2 controlled
by the electronic properties of a remote pyridine ring, pre-
paration of cyclopropane carboxylic acid 3 via a Corey-
Chaykovsky cyclopropanation, and a short synthesis of
sulfonamide 5.
(1) Kobayashi, T.; Narumiya, S. Prostaglandin Other Lipid Mediat 2002,
68-69, 557.
(2) For references supporting the use of EP4 antagonists to treating
inflammation see: (a) McCoy, J. M.; Wicks, J. R.; Audoly, L. P. J. Clin.
Invest. 2002, 110, 651. For atherosclerosis see: (b) Cipollone, F.; Fazia, M.
L.; Iezzi, A.; Cuccurullo, C.; De Cesare, D.; Ucchino, S.; Spigonardo, F.;
Marchetti, A.; Buttitta, F.; Paloscia, L.; Mascellanti, M.; Cuccurullo, F.;
Mazzetti, A. Arterioscler., Throm., Vasc. Biol. 2005, 25, 1925. For cancer see:
(c) Yang, L.; Huang, Y.; Porta, R.; Yanagisawa, K.; Gonzalez, A.; Segi, E.;
Johnson, D. H.; Narumiya, S.; Carbone, D. P. Cancer Res. 2006, 66, 9665. (d)
Chell, S. D.; Witherden, I. R.; Dobson, R. R.; Moorghen, M.; Herman, A.
A.; Qualthrough, D.; Williams, A. C.; Paraskeva, C. Cancer Res. 2006, 66,
3106. (e) Ma, X.; Kundu, N.; Rifat, S.; Walser, T.; Fulton, A. M. Cancer Res.
2006, 66, 2923.
(3) Burch, J. D.; Belley, M.; Fortin, R.; Deschenes, D.; Girard, M.;
Colucci, J.; Farand, J.; Therien, A. G.; Mathieu, M.-C.; Denis, D.; Vigneault,
E.; Levesques, J.-F.; Gagne, S.; Wrona, M.; Xu, D.; Clark, P.; Rowland, S.;
Han, Y. Bioorg. Med. Chem. Lett. 2008, 18, 2048.
(4) (a) Anderson, K. K. In Comprehensive Organic Chemistry; Jones, D. N.,
Ed.; Permagon Press: Oxford, UK, 1979; Vol. 3, pp 317 and 345. (b) Graham, S.
L.; Sholtz, T. H. Synthesis 1986, 852. (c) De Vleeschauwer, M.; Gauthier, J. Y.
Synlett 1997, 375. (d) Huang, H.-C.; Reinhard, E. J.; Reitz, D. B. Tetrahedron
Lett. 1994, 35, 7201. (e) Chan, W. Y.; Berthelette, C. Tetrahedron Lett. 2002, 43,
4537.
(5) Baskin, J. M.; Wang, Z. Tetrahedron Lett. 2002, 43, 8479.
(6) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R. Tetrahedron
2001, 57, 2469.
(7) A safety evaluation for this reaction was not done. For the use of
tungsten-catalyzed oxidation on large scale see: (a) Gauthier, D.; Desmond R.;
Devine, P. WO2006/040155. (b) Roy, A.; Gosselin, F.; O'Shea, P. D.; Chen, C.-y.
J. Org. Chem. 2006, 71, 4320. (c) Dolman, S. J.; Gosselin, F.; O'Shea, P. D.;
Davies, I. W. Tetrahedron 2006, 62, 5092.
Prostanoids are a group of lipid mediators that regulate
numerous processes in the body. Prostaglandin E2 (PGE2) is
the principal proinflammatory prostanoid and it plays cru-
cial roles in several biological events such as neuronal func-
tion, female reproduction, vascular hypertension, tumorige-
nesis, kidney function, and inflammation.1 PGE2 mediates
its various cellular functions through binding to the various
subtypes of prostaglandin E receptors, namely EP4. This
inhibition has recently been proposed as a new approach to
the treatment of chronic ailments such as arthritis.2 Our
discovery efforts identified quinoline MF-310 as a potent,
selective inhibitor of the EP4 receptor and a promising lead
DOI: 10.1021/jo901267x
r
Published on Web 08/07/2009
J. Org. Chem. 2009, 74, 6863–6866 6863
2009 American Chemical Society

Molinaro et al.
JOCNote
SCHEME 1. Retrosynthetic Plan for EP4 Antagonist MF-310
SCHEME 3. Synthesis of Cyclopropane Carboxylic Acid 3a
aReagents and conditions: (a) n-BuLi, CuI, ClCOCO2Me, 81%;
(b) Me3Al, DCE, 78%; (c) p-TsOH, PhMe, 95%; (d) Me3SOI,
t-BuOK, DMSO, 95%; (e) TMSOK, THF, 65 °C, 95%.
SCHEME 4. Synthesis of Succinimide 2a
aReagents and conditions: (a) EtOH, H2SO4, reflux, 78%; (b)
diethyl succinate, NaOEt, EtOH/PhMe, reflux, 69%; (c) (1)
CF3CH2OTf, K2CO3, DMF, 70 °C, (2) water, 94%; (d) 5 N
NaOH, THF, reflux, 100%; (e) TFAA, PhMe, 0 °C, 89%; (f) (1)
sulfonamide 5, TFA, THF, reflux, (2) heptane, 84%.
SCHEME 2. Synthesis of Sulfonamide 5a
depend on the rapid addition of acrylate to a mixture of
t-BuOK and Me3SOI (i.e., addition time of <3 min) and in
maintaining the internal temperature near 40 °C. This protocol
provided cyclopropane ester 16 in 95% yield. Intermediate 16
could be isolated and purified by a direct recrystallization from
the reaction mixture by adding water. The final hydrolysis step
to provide 1.79 kg of cyclopropane carboxylic acid 3 was
performed with TMSOK,10 which reached completion in 3 h
in contrast to a hydroxide-mediated protocol that required
3 days to achieve >95% conversion.
Succinimide 2 was prepared in 6 steps from commercially
available pyridine dicarboxylate 7 (Scheme 4). After a Fisher
esterification to prepare the diethyl ester of 2,3-pyridine
dicarboxylate 17 and a Claisen condensation with diethyl
succinate to afford the requisite dihydroxyquinoline 18, the
crude reaction mixture was solvent switched from toluene
to DMF and used directly in the alkylation step with
CF3CH2OTf. At the end of the alkylation step, intermediate
19 was isolated in 51% yield from pyridine dicarboxylate 7 (3
steps) and high purity (>98A%)11 by a slow crystallization
of the crude reaction mixture from DMF:water. A subse-
quent hydrolysis of 19 from NaOH in THF provided diacid
20 in quantitative yield. While prolonged reaction time at
80 °C with Ac2O as a solvent did allow for the successful
dehydration to form anhydride 4, a protocol with 5 equiv of
TFAA in toluene at 0 °C was preferred for large-scale pre-
paration. This protocol allowed for a dramatic rate enhance-
ment (99% conversion in 30 min) and the residual TFAA
was easily removed by distillation. Finally, clean conversion
to succinimide 2 from anhydride 4 and sulfonamide 5 was
aReagents and conditions: (a) HS(CH2)2CO2Me, K2CO3, n-Bu4-
NBr, PhMe, 95%; (b) H2O2, NaWO4, n-Bu4NSO4, PhMe/water,
45 °C, 95%; (c) (1) NaOMe, MeOH, 0 °C, (2) H2NOSO3H/
KOAc, water, 77%; (d) H2 (80 psi), PtO2, 1,4-dioxane/H2O,
45 °C, 78%.
aging at ambient temperature to afford 2,4-dimethylnitroben-
zene. On large scale this was avoided by monitoring the tem-
perature during the deprotonation step by a portion-wise
addition of base, followed by an in situ subsequent reaction with
aqueous hydroxylamine-O-sulfonic acid to afford nitro sulfon-
amide 12 in 77% yield.8 Finally, PtO2-catalyzed reduction
afforded 1.25 kg of requisite aniline 5 in 78% yield (Scheme 2).
Cyclopropane carboxylic acid 3 was prepared in 5 steps
from dimethoxybenzene 6 (Scheme 3). Ortho metalation of
1,3-dimethoxybenzene with n-BuLi, followed by formation
of the corresponding cuprate and quenching with methyl
oxalylchloride afforded the aryl oxylate 13 in 81% yield. The
methyl-ester analogues were used in place of the ethyl option
as this afforded more crystalline intermediates, facilitating
purification. Although a Wittig olefination of 13 was possi-
ble, rejection of the triphenylphosphine oxide byproduct
proved difficult on larger scale. Therefore, the olefination
of ketone 13 was replaced with a two-step Me3Al addition
and acid-catalyzed dehydration sequence to provide acrylate
15 in 74% yield over 2 steps. The success of the subsequent
Corey-Chaykovsky cyclopropanation9 was found to
(8) No experiments were conducted to determine the pKa values or the
order of deprotonation. However, we believe it to be reversible.
(9) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(10) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(11) A% indicates the area percent observed on a HPLC trace at 220 nm.
Yields are reported relative to an HPLC standard.
6864 J. Org. Chem. Vol. 74, No. 17, 2009

Molinaro et al.
JOCNote
TABLE 1. Regioselective Reductions of Succinimide 2
FIGURE 1. Regioselective azaphthalimide reduction.
achieved with 5 equiv of TFA in THF. The product could be
precipitated out by the addition of heptane as an antisolvent
providing 5.34 kg of 2 in 84% yield. It should be noted that 2
was isolated as a 3:2 THF solvate, which influenced the
efficacy of the next transformation (vide infra). The THF
could be removed by heating the material under vacuum at
temperatures above 110 °C (Scheme 4).
The next challenge to be addressed was the critical regio-
selective succinimide reduction. The regioselective reduction
of azaphthalimides having the general structure A (Figure 1)
has been described by using Mg(ClO4)2 in conjunction with
NaBH4;12 however, we are not aware of examples in the
literature of this type of selectivity being extended to sub-
strates such as B with an aryl spacer between the pyridine and
succinimide functionalities. While chelation between the
pyridine nitrogen atom and the proximal carbonyl has been
invoked by Goto et al.12 to explain the selectivity observed
with the reduction of A in the presence of Mg2þ ions, this is
not possible with compounds such as B where any observed
selectivity would arise from differences in electronics be-
tween the two carbonyls.
A number of reduction conditions of succinimide 2 were
evaluated in order to identify a selective protocol for the pre-
parationofregioisomer21over 22 (Table1). Ofthereductants
tested, lithium thexylborohydride (LTB) and diisobutyl-
aluminum hydride (DIBAL) showed promising selectivities
(entries 5 and 6). While the reduction with LTB showed good
yield and selectivity (80% yield, dr=5:1, entry 5), the limited
commercial availability of the reducing agent precluded the
use ofthisprotocolon larger scale. Onthe otherhand, DIBAL
afforded a low yield of the desired regioisomer, but with
greater selectivity (35% yield, dr=10:1, entry 6), probably
due to a preferential binding to one of the carbonyls. In
toluene, a relatively large excess of DIBAL (4.7 equiv) was
required to achieve complete conversion of the starting ma-
terial, with modest yield (entry 6). In addition to the regio-
isomer 22 (7A%),11 an over reduced byproduct 23 (9A%)11
was also formed during this reaction due to the large excess of
DIBAL required to achieve complete conversion of 2. Pre-
sumably, some of the excess reagent may be necessary to
deprotonate the sulfonamide, as well as for coordination to
the other Lewis basic sites in the molecule. In an effort to
minimize the requirements in DIBAL, a variety of sacrificial
nonreductive Lewis acids were screened. While the number of
equivalents of DIBAL could be reduced by using an addi-
tional Lewis acid such as Et2Zn or Et3Al (entries 7 and 8), this
resulted only in a marginal improvement inyields. A varietyof
solvents were evaluated for this reaction and the use of
chlorobenzene led to a significant improvement in the HPLC
profile of the reaction with a substantial improvement in the
yield (67%) with 3.4 equiv of DIBAL (entry 9). In this solvent,
there was no advantage of adding Et3Al or Et2Zn. While
the use of THF as a solvent led to a number of unidentified
side products and low yields, we were pleased to find that the
reduction of the partial THF solvate of 2, isolated from the
aniline/anhydride condensation, led to higher yields of 21
(entry 12 vs. 9). Although we remain uncertain of the exact
role of THF on the reduction of 2, the optimum amount
required is 0.7 equiv (entries 10-12). Furthermore, during the
course of this reaction we have observed an increase in ratios
of regioisomers (21 vs. 22).13 We believe that 22 is preferen-
tially converted to 23 under these conditions therefore slightly
increasing the final ratio of the reaction. Finally, on 3.07 kg
scale, the excess hydride in the reaction mixture was quenched
with acetone in order to minimize hydrogen gas evolution
during aqueous workup. An extraction with a 3 M solution of
tartaric acid was performed at 45 °C in order to remove
aluminum salts and minimize emulsions in the workup of this
reaction. The isolated product 21 was shown to be 76A%,
with the major impurities being the regioisomer 22 (7A%)11
and the over-reduction product 23 (12A%).11,14
Completion of the synthesis for MF-310 is outlined in
Scheme 5. The crude hydroxy lactam 21 (4.00 kg) was further
reduced to lactam 24 with 5 equiv of triethylsilane dissolved
in a mixture of CH2Cl2 and TFA (1:1) and refluxed for 5 h.15
This procedure afforded a 90% yield of the lactam 24.
Treatment with activated charcoal was necessary at this
stage to remove the dark color and increase the purity profile
from 70A% to 75A% as shown by HPLC analysis. The
purity of lactam 24 was further increased with two subse-
(13) Ratios of 21:22 as a function of conversion of 2: 20% (7:1), 65% (9:1),
100% (11:1).
(14) A total of 5A% of minor unidentified byproduct was also observed.
(15) Only the alcohol functionality is reduced by the Et3Si/TFA condi-
tions providing products 24, 25, and 26.
(12) Goto, T.; Konno, M.; Saito, M.; Sato, R. Bull. Chem. Soc. Jpn. 1989,
62, 1205.
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Molinaro et al.
JOCNote
SCHEME 5. Synthesis of MF-310a
Experimental Section
1-(3-Methyl-4-nitrophenyl)methanesulfonamide (12). A 100 L
reaction vessel equipped with a N2 inlet, thermocouple, mechan-
ical stirrer, and an addition funnel was charged with methanol
(41.6 L) and cooled to 0 °C. Then, a solution of NaOMe 30 wt %
in MeOH (4.32 L, 23.28 mol) and sulfone 10 (5.85 kg, 19.40 mol)
was charged and the resulting slurry was aged for 2.5 h. Next,
a solution of NH2OSO3H (5.49 kg, 48.50 mol) and KOAc
(5.14 kg, 52.40 mol) in water (27.7 L) was added to the reaction
mixture over 1.5 h while keeping the internal temperature
<5 °C and then allowed to slowly warm to rt overnight. The
resulting slurry is filtered and the solids washed with water (2 ꢀ
8 L) in a pressure filter. After transfer to a filter pot, the solids
are washed with additional water (4 ꢀ 8 L) followed by toluene
(3 ꢀ 8 L) and dried on a frit under a nitrogen atmosphere for
20 h, followed by tray drying in a vacuum oven at 24 °C and
8 Torr for an additional day: 7.19 kg of 12 at 48 wt % was
isolated (14.98 mol, 77% yield): 1H NMR (400 MHz, MeOD-
d4) δ 7.96 (d, J=8.3 Hz, 1H), 7.50-7.46 (m, 2H), 4.82 (s, 3H),
4.40 (s, 2H), 2.58 (s, 3H); 13C NMR (100 MHz, MeOD-d4)
δ 150.7, 137.5, 136.4, 134.7, 130.7, 125.8, 61.0, 20.3; IR
(CHCl3) 3368, 3261, 3020, 2988, 1614, 1519, 1339, 1297,
1269, 1215, 1172, 1155, 1130, 931, 843, 756, 669 cm-1; HRMS
ESI (m/z) [M þ H]þ calcd for C8H11N2O4S 231.0434, found
231.0436.
aReagents and conditions: (a) (1) Et3SiH, TFA, DCE, 90%, (2)
MeOH/0.1 N HCl recrystallization, 83%, (3) CH3CN/0.1 N
HCl recrystallization, 88%; (b) (1) 3, EDC-HCl, DMAP,
CH3CN, 92%, (2) CH3CN/0.1 N HCl recrystallization, 81%;
(c) NaOH, H2O, THF, heptane, 91%.
SCHEME 6. Byproducts 25, 26, 27, and 28 Observed
quent crystallizations: once from MeOH/0.1 N HCl and
once from CH3CN/0.1 N HCl with 83% and 88% recovery,
respectively. This afforded material which was 89A% with
4A% of both regioisomer 25 and isoindoline 26.11 Coupling
sulfonamide 24 with cyclopropane carboxylic acid 3 using
EDC-HCl in CH3CN afforded a 92% yield of MF-310 free
acid,16 which was recrystallized from CH3CN by using 0.1 N
HCl as an antisolvent to afford 3.25 kg of material that was
shown to be 97A%, contaminated with 1.6A% of regio-
isomer 27 and 0.9A% of 28 (Scheme 6).11
1-{4-[8-Hydroxy-6-oxo-5,9-bis(2,2,2-trifluoroethoxy)-6,8-di-
hydro-7H-pyrrolo[3,4-g]quinolin-7-yl]-3-methylphenyl}methane-
sulfonamide (21). A 100 L reaction vessel equipped with an N2
inlet, thermocouple, mechanical stirrer, and an addition funnel
was charged with the succinimide 2 (3.07 kg, 5.12 mol), chloro-
benzene (60 L), and THF (125 mL, 1.54 mol). The mixture was
cooled to -8 °C and a solution of 1.5 M DIBAL in toluene
(11.6 L, 17.4 mol) was added over 1.5 h causing the internal
temperature to rise to -4 °C. The mixture was aged 15 min.
Acetone (3 L) was added over 5 min with the internal tempera-
ture rising to 3 °C. The mixture was aged 30 min and then
transferred into an extractor containing aqueous 3 M tartaric
acid (30 L). The internal temperature rose to 35 °C. The mixture
was warmed to 45 °C and aged 30 min. The layers were separated
and the aqueous layer was back extracted with MTBE (15 L).
The crude organic solutions were filtered through a pad of Solka
Floc and washed with chlorobenzene (3 ꢀ 4 L). The combined
organic layers were assayed at 2.24 kg (76% yield) with a 11:1
mixture of regioisomers. The desired hydroxyl lactam was
A number of conditions were evaluated in an effort to
identify a practical approach to the salt formation. A series
of water miscible solvents were examined by using basic
aqueous solutions as antisolvents. Surprisingly, many of
these conditions returned the free acid. For example, dissol-
ving the free acid MF-310 in DME and adding 0.1 N NaOH
effected slow precipitation of the free acid in ∼80% recovery.
The nature of this material was characterized by X-ray
1
powder diffraction and H NMR. We were pleased to find
1
76A%. H NMR (500 MHz, acetone-d6) δ 9.10 (d, J = 4.14
that dissolving the free acid in THF and adding 1.3 equiv of 5
N NaOH allowed for the isolation of the sodium salt of MF-
310. Heptane was added as an antisolvent and the resulting
suspension was filtered to afford 2.15 kg of the sodium salt of
MF-310 in 87% yield (98A%). The material was contami-
nated with low levels of the sodium salts of 27 (1.1A%) and
28 (0.6A%).11
In conclusion, a practical large-scale chromatography-
free synthesis of EP4 antagonist MF-310, a potential new
treatment for chronic inflammation, was developed. The
synthetic route provided MF-310, as its sodium salt, in
10 steps and 17% overall yield from commercially available
pyridine dicarboxylate 7. The key features of this sequence
include a unique regioselective reduction of succinimide 2
controlled by the electronic effects of a remote pyridine ring,
preparation of cyclopropane carboxylic acid 3 through a
Corey-Chaykovsky cyclopropanation, and a short synthe-
sis of sulfonamide 5. This approach was used to successfully
produce >2.0 kg of MF-310 Na salt.
Hz, 1 H), 8.76 (d, J=8.6 Hz, 1 H), 7.77 (dd, J=8.6, 4.3 Hz, 1 H),
7.46-7.36 (m, 3 H), 6.60 (d, J=8.3 Hz, 1 H), 6.24 (s, 2 H), 6.16
(d, J=8.3 Hz, 1 H), 5.33-5.16 (m, 3 H), 5.06-4.94 (m, 1 H), 4.37
(s, 2 H), 2.30 (s, 3 H); 13C NMR (100 MHz, acetone-d6) δ 163.6,
152.7, 148.5, 146.2, 145.1, 138.3, 136.1, 134.3, 134.0, 133.3,
131.9, 129.9, 129.0, 126.0, 124.9 (q, J = 277 Hz), 124.8 (q,
J = 277 Hz), 123.3, 117.9, 82.8, 72.5 (q, J = 35 Hz), 71.0 (q,
J=35 Hz), 60.9, 18.4; 19F NMR (377 MHz, acetone- d6) δ -78.9
(t, J=8.7 Hz), -78.8 (t, J=8.9 Hz); IR (neat) 1685, 1500, 1372,
1263, 1153, 1094, 1040, 959 cm-1; HRMS ESI (m/z) [M þ H]þ
calcd for C23H20N3O6F6S 580.0965, found 580.0971; mp 128.3-
130.2 °C.
Acknowledgment. We thank Dr. Robert Reamer and
Dr. Laird Trimble for NMR support, Dr. Chad Dalton for
X-ray powder diffraction analysis, and Dr. Wayne Mullett
and Mr. Claude Briand for analytical support.
Supporting Information Available: Experimental procedures
and spectroscopic data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Measured pKa for MF-310 is 5.6.
6866 J. Org. Chem. Vol. 74, No. 17, 2009